The present invention relates to the delivery of active agents across or into a porous surface by ultrasound phonophoresis. Such a surface includes any interface which may be provided with microscopic channels or irregular spaces extending at least partially therethrough. Examples of present significance are human and animal skin, egg shells, certain vegetables, and printable cellulosic surfaces.
Ultrasound in the lower megahertz frequency range is used for diagnostic imaging, physiotherapy, hyperthermia and phonophoresis. Ultrasound-induced phonophoresis embraces, inter alia the transfer of biologically active agents (or chemical substances) at an enhanced rate through the skin or other porous surfaces. According to Williams, (Ultrasonics 1990, 28, 137-141) who tested three topical anaesthetic agents on the skin, phonophoresis did not occur if temperature effects were eliminated (i.e. he claims that enhanced diffusion rates were due simply to the temperature rise caused by sonication). Referring to some eighty previous reports, Williams et al in the same paper but at pages 132-136 state xe2x80x9ca critical evaluation of the small number of observations on which these articles are based shows the inherent variability of the technique was so large that the observed distribution of results could simply have arisen by statistical chancexe2x80x9d. It can be concluded that as widely understood phonophoresis, if it occurs at all, is generated by moving an ultrasound activated transducer over the skin, and in contact with it, using a coupling gel or cream containing the material/drug that it is desired to deliver into the subdermal region. Clearly Williams raises strong doubts about the genuine nature of ultrasound-induced phonophoresis occuring under such circumstances. A recent patent [U.S. Pat. No. 5,421,816 Lipkovker] approaches the problem of transdermal drug delivery differently, but envisages a porous polymeric membrane enclosing the drug and the membrane is in contact with the skin. As we shall show in the following investigation efficient transfer using ultrasound preferably requires an aqueous solution of the drug which it is desired to deliver, to be in complete contact with the skin so that microbubbles generated by ultrasound can lodge on the skin close to hair follicles and sweat glands. The actions and properties of these acoustically induced bubbles are responsible for driving drugs at high transfer rates into porous surfaces.
Bearing in mind the desirability of being able to deliver certain biologically active agents such as drugs and anaesthetic preparations, in reasonable time scales, preferably in a period of a few seconds, without mechanically penetrating the skin or shell with a hypodermic needle, for example, plainly requires other mechanisms to achieve topical transfer.
Similarly there is commercial interest in the transfer into incubating chicken, duck and turkey eggs of various biologically active agents, for example Tylosin tartrate and Gentamycin, for control of Mycoplasma gallisepticum and Mycoplasma meleagridis respectively. Additionally there is an interest in transferring through intact egg shells antibacterial drugs of other types, live viral vaccines, hyperimmnune serum and nutrient supplements. Administration of an antibiotic to act against egg-transmitted infectious agents already has great value even though it currently requires puncturing the shell.
The treatment of incubating avian eggs by embryonal vaccination or the introduction of antibiotics by penetrative means has been described in U.S. Pat. Nos. 4,604,968, 4,458,630 and 4,681,063.
An instrument using penetration of the eggshell (Sharma et al., Disease control in Avian Species by Embryonal Vaccination U.S. Pat. No. 4,458,630) by mechanical means is marketed in the USA where the poultry industry has a turnover in excess of $20 billion. Mechanical penetration of the shell is undesirable as it may transfer infection between eggs and requires the needle to be repeatedly sterilised. Notwithstanding this, claims for improved effects of in ovo vaccination are making the procedure popular in the poultry industry. The possibility of ensuring pathogen free stock has obvious attractions. Transfer of food and vitamin supplements in ovo, leading to more rapid turnover of stock is financially attractive. From the Journal International Hatchery Practice, 1991, 5 No. 7, 5-9 it is clear that in ovo injection leads to increased hatchability, improved disease resistance, higher growth rates and yield, reduced chick stress and reduced early mortality.
In ovo vaccination improves the protective capability of vaccines by placing them in the embryo at a time when they can stimulate good immunity against disease challenge at an early stage. Accordingly, if the instrument disclosed above could be utilised without perforation of the shell a sustantial advantage should be achieved. However an effective method must introduce the required quantity of materials in time scales that ideally permit thousands of eggs per hour to be treated. Further it is an ongoing problem to print indicia upon cellulosic film and other covering materials utilised in the preparation and storage of food.